BPH is characterised by the non-cancerous enlargement of the prostate gland, primarily thought to be driven by dihydrotestosterone (DHT), a metabolite derived from testosterone through the action of the enzyme 5-alpha reductase.²

At the age of 60, ~50% of men present with microscopic BPH, which increases to ~90% among 85-year-olds. However, only about half of individuals with this histological indication will exhibit a noticeable enlargement of the prostate gland. Furthermore, among those with an enlarged gland, ~50% will develop symptoms associated with BPH.²

BPH frequently manifests as lower urinary tract symptoms (LUTS). The prevalence of LUTS is between 10%-30% for men in their 60s and 70s, and 30% in their 80s. While LUTS due to BPH can significantly impair individuals' quality of life, it is noteworthy that not all men with BPH necessarily experience these symptoms, and conversely, not all men with LUTS have underlying BPH.^2,3

Long-term complications of BPH include acute urinary retention (AUR), recurrent urinary tract infections, bladder stones, and post-obstructive kidney failure. AUR is one of the most common complications, with a risk reaching up to 14% over a decade in patients exhibiting large prostates and moderate to severe symptoms.²

 8 warning signs of BPH and causes

Symptoms associated with BPH commonly arise due to either a narrowed urethra or an overtaxed bladder, both resulting from the obstruction caused by the enlarged prostate. Symptoms suggestive of BPH include:⁴

1. Urinary frequency - urination eight or more times a day.
2. Urinary urgency - the inability to delay urination.
3. Trouble starting a urine stream.
4. A weak or an interrupted urine stream.
5. Dribbling at the end of urination.
6. Nocturia - frequent urination during periods of sleep urinary retention.
7. Urinary incontinence - the accidental loss of urine.
8. Pain after ejaculation or during urination urine that has an unusual colour or smell.

The cause of BPH is not well understood. Throughout their lifespan, men produce both testosterone, commonly known as a male hormone, and small quantities of oestrogen. However, as men age, the level of active testosterone in their bloodstream decreases, leading to a higher proportion of oestrogen.⁴

Studies have suggested that this shift in hormonal balance may contribute to the development of BPH by enhancing the activity of substances that stimulate the growth of prostate cells.⁴

As mentioned, it has been hypothesised that BPH is driven by DHT, which play an important role in prostate development and enlargement. Despite declining testosterone levels, older men often maintain elevated levels of DHT in their prostates. This accumulation of DHT might promote the continued growth of prostate cells. Notably, researchers have observed that men lacking DHT production do not develop BPH.⁴

BPH risk factors

Apart from age, risk factors for developing BPH include the presence genetics, a lifestyle factors, and metabolic syndromes including diabetes as well as obesity. Genetic factors play a significant role, with evidence indicating a strong hereditary component to BPH risk, particularly among male relatives. Male relatives and brothers have a 4- and 6-fold increased risk, respectively.³

Lifestyle factors, such as diet, physical activity, and alcohol consumption, significantly influence BPH progression. Dietary patterns rich in certain macronutrients and micronutrients may impact BPH risk.³

Evidence suggest that both macronutrients and micronutrients might influence the risk of BPH, though findings are somewhat inconsistent. When it comes to macronutrients, higher total energy intake, energy-adjusted total protein intake, consumption of red meat, fat, milk and dairy products, cereals, bread, poultry, and starch have all been linked to potentially increased risks of clinical BPH and BPH surgery. Conversely, intake of vegetables, fruits, polyunsaturated fatty acids, linoleic acid, and vitamin D may potentially decrease the risk of BPH.³

Regarding micronutrients, higher levels of circulating vitamin E, lycopene, selenium, and carotene have shown inverse associations with BPH. However, zinc's association with BPH risk appears to be more complex, as it has been linked to both increased and decreased risk in different studies. The good news is that increased physical activity and moderate alcohol intake have been linked to decreased BPH risk.³

Metabolic syndrome components, including obesity, diabetes, and disruptions in glucose homeostasis, are associated with increased prostate volume and heightened BPH risk. Obesity, in particular, is consistently linked to prostate enlargement and an elevated risk of urinary symptom progression and BPH-related interventions. While associations between lipids and BPH remain less explored, evidence suggests potential correlations.³

How is BPH managed?

BPH typically progresses slowly, with severe complications being rare. For those with mild symptoms, a watchful waiting approach alongside lifestyle adjustments, such as regular physical activity, may suffice. While clinicians often recommend avoiding irritants like coffee and alcohol, evidence supporting these suggestions is scant.²

While surgery (transurethral resection of the prostate [TURP]) is the gold standard for managing BPH, medical therapy is often favoured over surgical intervention in older men when feasible. Pharmacotherapy selection should consider patient age, symptoms, prostate size, comorbidities, and potential adverse effects like ejaculatory dysfunction and changes in blood pressure.^2,5,6

The 2023 updated American Urology Association (AUA) guidelines recommend alpha blockers as first-line treatment for individuals living with moderate to severe symptoms, offering choices such as tamsulosin.⁶

For patients with prostatic enlargement, 5-ARIs are recommended for symptom improvement and to prevent progression or reduce the risk of urinary retention and future surgery. These inhibitors may also be considered to reduce bleeding and the need for blood transfusion after surgical interventions like TURP.⁶

For AUR due to BPH, oral alpha blockers should be prescribed before a voiding trial, and patients newly treated for AUR should complete at least three days of medical therapy before attempting a trial without a catheter.⁶

When is combination treatment indicated?

According to the AUA, combination therapy, particularly 5-ARIs with alpha blockers, should be offered to patients with demonstrable prostatic enlargement and predominant storage symptoms.⁶

The use of tamsulosin for LUTS due to BPH provides a rapid response, manifesting as a significant reduction in both storage and voiding symptoms within hours or days compared to placebo. Clinical trials have shown that tamsulosin improves symptom scores by 20% to 48% and increases maximum flow rate (Q-max) by 13% to 44%.⁷

On the other hand, 5-ARIs like dutasteride induce apoptosis of prostatic cells by suppressing DHT levels, leading to a reduction in prostate volume. Dutasteride significantly reduces serum DHT levels by 95%, resulting in a reduction of 94–97% of DHT levels in the prostate. Dutasteride treatment for six to 12 months reduces prostate size by 18%–28%, decreases circulating prostate-specific antigen (PSA) levels by 50% and increases Q-max by 1.5–2.0 ml/s in patients with BPH-associated bladder outlet obstruction.⁷

How effective is combination therapy with dutasteride/tamsulosin?

The Combination of Avodart® and Tamsulosin (CombAT) study investigated the efficacy of combination therapy with dutasteride/tamsulosin compared to monotherapy in men with moderate-to-severe LUTS due to BPH and prostatic enlargement.¹

Conducted over four years, this multi-centre, randomised, double-blind study included 4844 men aged ≥50-years with a clinical diagnosis of BPH, International Prostate Symptom Score (IPSS) of ≥12, prostate volume of ≥30cm³ or greater, PSA levels between 1.5-10ng/ml, and Q-max between 5-15 ml/s with a minimum voided volume of 125ml.¹

Participants were randomly assigned to receive oral daily doses of tamsulosin (0.4mg) or dutasteride (0.5mg), or a combination of both agents. The primary endpoint was the time to first AUR or BPH-related surgery, while secondary endpoints included BPH clinical progression, symptoms, Q-max, prostate volume, safety, and tolerability.¹

The results showed that combination therapy with dutasteride/tamsulosin was significantly more effective than tamsulosin monotherapy in reducing the relative risk of AUR or BPH-related surgery. Combination therapy was also superior to both monotherapies in reducing the relative risk of BPH clinical progression.¹

Additionally, combination therapy provided greater symptom relief compared to monotherapy at the four-year mark. The safety and tolerability profile of combination therapy were consistent with previous experiences with dutasteride and tamsulosin monotherapies.¹

The authors concluded that their results support the long-term use of combination therapy with dutasteride/tamsulosin for men with moderate-to-severe LUTS due to BPH and prostatic enlargement.¹

Timing of combination therapy initiation

D'Agate conducted a study to assess the impact of delaying the initiation of combination therapy with dutasteride 0.5mg and tamsulosin 0.4mg on the risk of AUR or BPH-related surgery in patients with moderate-to-severe LUTS at risk of disease progression.⁸

Using data from Phase III/IV dutasteride trials, they employed clinical trial simulations to evaluate the risk of AUR or BPH-related surgery over 48 months in patients with moderate-to-severe LUTS/BPH who did not respond to tamsulosin monotherapy. Various simulation scenarios were explored, including immediate start and delayed start of combination therapy (ranging from one to 24 months).⁸

The results showed that patients who initiated combination therapy at months one or three did not exhibit significantly different outcomes compared to those who started immediately. However, a notable difference was observed in patients who switched to combination therapy after ≥ 6 months from the initial treatment.⁸

By month 48, the incidence of AUR or BPH-related surgery was markedly lower (4.6%) in patients who received immediate combination therapy compared to those who switched after six, 12, or 24 months (9.5%, 11.0%, and 11.3%, respectively).⁸

In conclusion, initiating combination therapy before month six was associated with a significantly reduced risk of AUR/S compared to delaying treatment by ≥ 6 months. These findings suggest implications for the treatment approach in men with LUTS/BPH at risk of disease progression.⁸

Conclusion

The management of BPH presents a multifaceted challenge, particularly in ageing populations where its prevalence is high. Understanding the interplay of hormonal changes, genetic predispositions, and lifestyle factors is crucial for effective intervention. While BPH typically progresses slowly, complications such as AUR can have significant implications for patients' quality of life.

Combination therapy, notably with dutasteride/tamsulosin, has emerged as a promising approach to address the multifactorial nature of BPH. The CombAT study demonstrated the long-term efficacy of this combination in reducing the risk of AUR or BPH-related surgery, providing superior symptom relief compared to monotherapy. Additionally, D'Agate's study underscores the importance of timely initiation of combination therapy to mitigate disease progression risks.

Moving forward, integrating combination therapy into clinical practice, particularly in patients with moderate-to-severe BPH and prostatic enlargement, could enhance treatment outcomes and improve long-term prognosis. However, individualised approaches considering patient characteristics and preferences remain paramount in optimising BPH management strategies.

The reference list is available on www.medicalacademic.co.za.

References

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2. Franco JVA, Tesolin P, Jung JH. Update on the management of benign prostatic hyperplasia and the role of minimally invasive procedures. Prostate Int, 2023.
3. Lim KB. Epidemiology of clinical benign prostatic hyperplasia. Asian Journal of Urology, 2017.
4. National Institute of Diabetes and Digestive and Kidney Diseases. Prostate Enlargement (Benign Prostatic Hyperplasia). [Internet]. Available at: https://www.niddk.nih.gov/health-information/urologic-diseases/prostate-problems/prostate-enlargement-benign-prostatic-hyperplasia
5. Bortnick E, Brown C, Simma-Chiang V, Kaplan SA. Modern best practice in the management of benign prostatic hyperplasia in the elderly. Ther Adv Urol, 2020.
6. Sandhu JS, Bixler BR, Dahm P, et al. Management of lower urinary tract symptoms attributed to benign prostatic hyperplasia (BPH): AUA Guideline amendment 2023. J Urol, 2023.
7. Dimitropoulos K, Gravas S. Fixed-dose combination therapy with dutasteride and tamsulosin in the management of benign prostatic hyperplasia. Ther Adv Urol, 2016.
8. D'Agate S, Chavan C, Manyak M, et al. Impact of early vs. delayed initiation of dutasteride/tamsulosin combination therapy on the risk of acute urinary retention or BPH-related surgery in LUTS/BPH patients with moderate-to-severe symptoms at risk of disease progression. World J Urol, 2021.